Angiopoietin-like 4 protein (ANGPTL4) is a member of the angiopoietin like family of secreted proteins. It is a homooligomeric protein, capable of forming dimers and tetramers, that is expressed by cell types including macrophages, adipose, muscle, and liver cells. ANGPTL4 is also known as hepatic fibrinogen/angiopoietin-related protein (HFARP) (Kim et al. (2000) Biochem. J. 346:603-610); PPAR gamma angiopoietin related protein (PGAR)(Yoon, et al. (2000) Mol. Cell Biol., 20:5343-5349), and fasting induced adipose factor (FIAF)(Kerten et al. (2000) J. Biol. Chem., 275:28488-28493). ANGPTL4 contains an N-terminal coiled-coil domain and a C-terminal fibrinogen (FBN)-like domain (Kim et al. (2000) Biochem. J. 346:603-610).
Lipoprotein lipase (LPL) has a central role in lipoprotein metabolism which includes the maintenance of lipoprotein levels in blood and, through tissue specific regulation of its activity. The coiled-coil region of ANGPTL4 is known to inhibit lipoprotein lipase (LPL)-mediated triglyceride (TG) clearance. Therefore, ANGPTL4 loss-of-function mutations (e.g., as seen in human subjects), genetic deletions (e.g., as seen in transgenic mice), and antibody inhibition (e.g., as seen in mice and cynomolgus monkeys) are all observed to decrease plasma triglycerides. Furthermore, ANGPTL4 antibodies are also known to activate LPL. Conversely, ANGPTL4 injection into mice produces a rapid increase in circulating triglycerides and this is at a higher rate than the injection of angiopoietin-like protein 3 (ANGPTL3)(Yoshida et al. (2002) J Lipid Res 43:1770-1772).
The anti-ANGPTL4 antibodies and antigen binding fragments described in this invention initiate, promote, or enhance activation of LPL, e.g., by blocking ANGPTL4 inhibition of LPL, thereby decreasing plasma triglycerides. These antibodies are expected to prevent and ameliorate the acute and chronic manifestations of diseases characterized by elevated triglyceride levels, e.g., primary dyslipidemia, hypertriglyceridemia, metabolic syndrome, type II diabetes, and the like.